Inhibition of eIF2\u03b1 dephosphorylation accelerates pterostilbene-induced cell death in human hepatocellular carcinoma cells in an ER stress and autophagy-dependent manner

Chen-Lin Yu,Hui-Ling Chiou,Shun-Fa Yang,Tung-Wei Hung,Chia-Liang Lin,Yi-Hsien Hsieh

doi:10.1038/s41419-019-1639-5

Abstract

Hepatocellular carcinoma (HCC) is the one of the most common cancers worldwide. Because the side effects of current treatments are severe, new effective therapeutic strategies are urgently required. Pterostilbene (PT), a natural analogue of resveratrol, has diverse pharmacologic activities, including antioxidative, anti-inflammatory and antiproliferative activities. Here we demonstrated that PT inhibits HCC cell growth without the induction of apoptosis in an endoplasmic reticulum (ER) stress- and autophagy-dependent manner. Mechanistic studies indicated that the combination of salubrinal and PT modulates ER stress-related autophagy through the phospho-eukaryotic initiation factor 2α/activating transcription factor-4/LC3 pathway, leading to a further inhibition of eIF2α dephosphorylation and the potentiation of cell death. An in vivo xenograft analysis revealed that PT significantly reduced tumour growth in mice with a SK-Hep-1 tumour xenograft. Taken together, our results yield novel insights into the pivotal roles of PT in ER stress- and autophagy-dependent cell death in HCC cells.

Highlights

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer mortality worldwide[1]
PT inhibits the proliferation of HCC cells To assess the effects of PT with the chemical structure depicted in Fig. 1a on cell viability, HCC cell lines (Huh-7, SK-Hep-1, PLC/PRF/5, HA22T/VGH and HepG2) were treated with various concentrations of PT (0, 25, 50, 75 and 100 μM) for 24 h, and cell viability was determined through MTT assay (Fig. 1b), trypan blue exclusion assay (Fig. 1c) and colony formation assay (Fig. 1d)
These results suggest that PT inhibits the growth of HCC cells in an apoptosis-independent manner

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer mortality worldwide[1]. The mortality of HCC is high because of potential curative treatments being effective only at the early disease stages[2] and drug resistance being developed. Autophagy is a critical intracellular degradation mechanism responsible for trafficking aggregated proteins, damaged organelles and other undesirable cytoplasmic materials for lysosomal degradation under cellular stress[9]. Autophagy is a mechanism for cellular survival in periods of cellular stress; it can lead to programmed cell death-II under certain conditions[10]. The endoplasmic reticulum (ER) is a perinuclear organelle responsible for Ca2+ storage, proteins and lipid

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Results

Conclusion